1. Field
Exemplary embodiments of the present invention relates to the use of novel aminopyridine derivatives to prevent or treat cancer, and more particularly to novel aminopyridine derivatives or pharmaceutically acceptable salts thereof, and a pharmaceutical composition for preventing or treating cancer comprising the same.
2. Discussion of the Background
It has been shown by molecular and cell biological analyses that the expression of AIMP2 (ARS-interacting multi-functional protein 2) is induced by TGF-β and AIMP2 proteins translocate to nucleus where they inhibit the expression of c-myc, whereas genetic disruption of AIMP2 induces the over-expression of c-myc, leading to the hyperproliferation of alveolar epithelial cells of the lung which causes neonatal lethality (M. J. Kim, B.-J. Park, Y.-S. Kang, H. J. Kim, J.-H. Park, J. W. Kang, S. W. Lee, J. M. Han, H.-W. Lee, S. Kim, Nat. Genet. 34, 330-336, 2003).
Korean Patent Application No. 2005-110946 discloses that AIMP2 is a novel tumor suppressor with a function of enhancing TGF-β by signaling through directly interaction with Smad2/3, and its exon2-deleted form of splicing variants, namely AIMP2DX2, is expressed specifically in cancer cell lines and tissues. In addition, it was confirmed that the levels of AIMP2 were dramatically reduced regardless of TGF-β in the cells transfected with AIMP2DX2, demonstrating that the production of AIMP2DX2 inactivates AIMP2. Since AIMP2DX2 downregulates AIMP2 and is closely associated with cancer formation or progression, it was demonstrated that various types of cancers (such as lung cancer, liver cancer, skin cancer, breast cancer, renal cell carcinoma, and osteosarcoma) can be diagnosed based on the expression of AIMP2. Korean Patent Application No. 2005-110946 in its entirety is hereby incorporated by reference.
Korean Patent Application No. 2005-110946 discloses that AIMP2 is a novel tumor suppressor with a function of enhancing TGF-β signaling through direct interaction with Smad2/3, and its exon2-deleted form of splicing variants, namely AIMP2DX2, is expressed specifically in cancer cell lines and tissues. In addition, it was confirmed that the levels of AIMP2 were dramatically reduced regardless of TGF-β in the cells transfected with AIMP2DX2, demonstrating that the production of AIMP2DX2 inactivates AIMP2. Since AIMP2DX2 downregulates AIMP2 and is closely associated with cancer formation or progression, it was demonstrated that various types of cancers (such as lung cancer, liver cancer, skin cancer, breast cancer, renal cell carcinoma, and osteosarcoma) can be diagnosed based on the expression of AIMP2. Korean Patent Application No. 2005-110946 in its entirety is hereby incorporated by reference.
The AIMP2DX2 protein is a splicing variant of AIMP2 in which the second exon is deleted from the AIMP2 protein sequence. Sequences of the AIMP2 protein (312 aa version: AAC50391.1 or GI: 1215669; 320 aa version: AAH13630.1, GI: 15489023, BC013630.1) are found in the literatures (312 aa version: Nicolaides, N. C., et. al., Genomics 29 (2), 329-334 (1995)/320 aa version: Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences, Proc. Natl. Acad. Sci. U.S.A. 99 (26), 16899-16903 (2002)). Korean Patent Application No. 10-2003-0018424 discloses a cancer-treating effect of AIMP2 protein, and its description of AIMP2 protein is hereby incorporated by reference.
Moreover, AIMP2 facilitates apoptosis by activating p53 when DNA is damaged (Han J M, et. al., Proc Natl Acad Sci USA, 105: 11206-11211 (2008)). AIMP2-DX2 was found to cause cancer by compromising pro-apoptotic activity of AIMP2 through competitive binding to p53 and interruption of binding between AIMP2 and p53 (Choi J W, et al., PLOS GENETICS, 7(3):e1001351, 2011). Thus, the publication describes AIMP2-DX2 as a potential and novel target for anticancer agents.
The above information disclosed in this Background section is only for enhancement of understanding of the background of the inventive concept, and, therefore, it may contain information that does not form the prior art that is already known in this country to a person of ordinary skill in the art.